Abstract Heart failure is the most expensive chronic disease affecting millions of Americans. While there are several clinical tests used to manage heart failure, these tests do not adequately track degrees of heart failure, are insufficiently quantitative, or require significant expertise. In particular, a biomarker of a key heart failure parameter, peripheral tissue perfusion and congestion, is lacking and sorely needed to help guide and stratify patient care. This application describes a novel, noninvasive method that samples the outermost epidermal layers of the palm that yields samples suitable for high-quality nuclear magnetic resonance (NMR)-based metabolomics. A cross-sectional pilot study provided preliminary data that there are significant differences in skin metabolites between the heart healthy and heart failure groups, supporting the central hypothesis that polar molecules in the outermost layers of the skin are sensitive predictors of the adequacy of blood flow. In the cross-sectional pilot study we noted individual differences unrelated to heart failure status, as manifested by greater variation in lactate between individuals than within an individual. To control for personal differences in epidermal profiles, we propose to measure lactate levels in individuals with advanced HF before and after placement of a left ventricular assist device (LVAD) or with cardiac resynchronization therapy (CRT) that dramatically augments tissue perfusion in HF patients. The aims proposed to test the central hypothesis are to (1) define the relationship of skin lactate levels with tissue perfusion in heart failure patients; and (2) to identify novel metabolic profiles in recuperating heart failure patients. The measurable outcomes will be the extent to which skin lactate and other metabolite levels correlate with symptom scores associated with heart function. The studies described in this application are the first to comprehensively determine the epidermal metabolome using NMR methods. If successful, this research could result in a new method of non-invasively assessing heart function and lays the groundwork for epidermal profiling to become part of clinical practice. More broadly, this study lays the groundwork for the use of epidermal metabolites to provide insight into any other disease that might manifest in the skin such as those associated with dry skin, cancer, or in-born errors of metabolism.